ABSTRACT Alcohol use disorder (AUD) affects approximately 10% of the western world population. Thus, the majority of people consume alcohol socially throughout adulthood without developing the disorder. This suggests the existence of endogenous homeostatic pathways that delay or prevent the development of AUD. We generated evidence to suggest that BDNF in the dorsolateral striatum (DLS) is part of such a homeostatic protective mechanism that keeps alcohol drinking in moderation. We further found that malfunctioning of BDNF signaling in the DLS, and in cortical regions, drives escalation of alcohol use. To date, we have been studying the function BDNF signaling in isolated corticostriatal brain regions. The next 5 years will be dedicated to examining the contribution of this pathway in the context of corticostriatal circuitries. Aim 1, will identify genes downstream of BDNF/TrkB signaling in DLS neurons that receive BDNF from the OFC, and will test their contribution to the gating of alcohol use. Aim 2 will test the hypothesis that microRNAs targeting BDNF in OFC neurons that project to the DLS contribute to the malfunctioning of BDNF signaling in the DLS resulting in escalation of alcohol use. Aim 3 will identify the target regions of BDNF mPFC neurons and examine the involvement of BDNF in these projections to the gating of alcohol seeking and compulsive alcohol drinking. To achieve these goals, we plan to combine state of the art molecular/genetic tools with mouse alcohol drinking paradigms. If successful, data generated from the studies will not only yield valuable information about the function and malfunction of BDNF signaling in corticostriatal circuitries but will also enable us to develop novel approaches to examine the contribution of other molecular signaling pathways in a specific circuitry to alcohol drinking behaviors. RELEVANCE (See instructions): NA for this submission.